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International Journal of Molecular... May 2024Astronauts on exploratory missions will be exposed to galactic cosmic rays (GCR), which can induce neuroinflammation and oxidative stress (OS) and may increase the risk...
Astronauts on exploratory missions will be exposed to galactic cosmic rays (GCR), which can induce neuroinflammation and oxidative stress (OS) and may increase the risk of neurodegenerative disease. As key regulators of inflammation and OS in the CNS, microglial cells may be involved in GCR-induced deficits, and therefore could be a target for neuroprotection. This study assessed the effects of exposure to helium (He) and iron (Fe) particles on inflammation and OS in microglia in vitro, to establish a model for testing countermeasure efficacy. Rat microglia were exposed to a single dose of 20 cGy (300 MeV/n) He or 2 Gy Fe (600 MeV/n), while the control cells were not exposed (0 cGy). Immediately following irradiation, fresh media was applied to the cells, and biomarkers of inflammation (cyclooxygenase-2 [COX-2], nitric oxide synthase [iNOS], phosphorylated IκB-α [pIκB-α], tumor necrosis factor-α [TNFα], and nitrite [NO]) and OS (NADPH oxidase [NOX2]) were assessed 24 h later using standard immunochemical techniques. Results showed that radiation did not increase levels of NO or protein levels of COX-2, iNOS, pIκB-α, TNFα, or NOX2 compared to non-irradiated control conditions in microglial cells ( > 0.05). Therefore, microglia in isolation may not be the primary cause of neuroinflammation and OS following exposures to helium or iron GCR particles.
Topics: Animals; Microglia; Cosmic Radiation; Oxidative Stress; Rats; Inflammation; Biomarkers; Nitric Oxide Synthase Type II; Iron; Cyclooxygenase 2; Helium; Tumor Necrosis Factor-alpha; NADPH Oxidase 2
PubMed: 38892109
DOI: 10.3390/ijms25115923 -
International Journal of Molecular... May 2024Alzheimer's disease (AD) is a devastating disorder with a global prevalence estimated at 55 million people. In clinical studies administering certain anti-beta-amyloid...
Alzheimer's disease (AD) is a devastating disorder with a global prevalence estimated at 55 million people. In clinical studies administering certain anti-beta-amyloid (Aβ) antibodies, amyloid-related imaging abnormalities (ARIAs) have emerged as major adverse events. The frequency of these events is higher among apolipoprotein ε4 allele carriers () compared to non-carriers. To reflect patients most at risk for vascular complications of anti-Aβ immunotherapy, we selected an APPswe/PS1dE9 transgenic mouse model bearing the human gene (APPPS1:E4) and compared it with the same APP/PS1 mouse model bearing the human gene ( ε3 allele; APPPS1:E3). Using histological and biochemical analyses, we characterized mice at three ages: 8, 12, and 16 months. Female and male mice were assayed for general cerebral fibrillar and pyroglutamate (pGlu-3) Aβ deposition, cerebral amyloid angiopathy (CAA), microhemorrhages, apoE and cholesterol composition, astrocytes, microglia, inflammation, lysosomal dysfunction, and neuritic dystrophy. Amyloidosis, lipid deposition, and astrogliosis increased with age in APPPS1:E4 mice, while inflammation did not reveal significant changes with age. In general, carriers showed elevated Aβ, apoE, reactive astrocytes, pro-inflammatory cytokines, microglial response, and neuritic dystrophy compared to carriers at different ages. These results highlight the potential of the APPPS1:E4 mouse model as a valuable tool in investigating the vascular side effects associated with anti-amyloid immunotherapy.
Topics: Animals; Alzheimer Disease; Disease Models, Animal; Mice, Transgenic; Mice; Humans; Female; Male; Amyloid beta-Peptides; Apolipoprotein E4; Presenilin-1; Amyloid beta-Protein Precursor; Cerebral Amyloid Angiopathy; Brain
PubMed: 38891941
DOI: 10.3390/ijms25115754 -
International Journal of Molecular... May 2024Suicide is a major public health priority, and its molecular mechanisms appear to be related to glial abnormalities and specific transcriptional changes. This study... (Review)
Review
Suicide is a major public health priority, and its molecular mechanisms appear to be related to glial abnormalities and specific transcriptional changes. This study aimed to identify and synthesize evidence of the relationship between glial dysfunction and suicidal behavior to understand the neurobiology of suicide. As of 26 January 2024, 46 articles that met the inclusion criteria were identified by searching PubMed and ISI Web of Science. Most postmortem studies, including 30 brain regions, have determined no density or number of total Nissl-glial cell changes in suicidal patients with major psychiatric disorders. There were 17 astrocytic, 14 microglial, and 9 oligodendroglial studies using specific markers of each glial cell and further on their specific gene expression. Those studies suggest that astrocytic and oligodendroglial cells lost but activated microglia in suicides with affective disorder, bipolar disorders, major depression disorders, or schizophrenia in comparison with non-suicided patients and non-psychiatric controls. Although the data from previous studies remain complex and cannot fully explain the effects of glial cell dysfunction related to suicidal behaviors, they provide risk directions potentially leading to suicide prevention.
Topics: Humans; Neuroglia; Suicide; Brain; Biomarkers; Autopsy; Suicidal Ideation; Bipolar Disorder
PubMed: 38891940
DOI: 10.3390/ijms25115750 -
International Journal of Molecular... May 2024Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive degeneration of upper and lower motor neurons (MNs) in the...
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive degeneration of upper and lower motor neurons (MNs) in the brain and spinal cord, leading to progressive paralysis and death. Increasing evidence indicates that neuroinflammation plays an important role in ALS's pathogenesis and disease progression. Neuroinflammatory responses, primarily driven by activated microglia and astrocytes, and followed by infiltrating peripheral immune cells, contribute to exacerbate/accelerate MN death. In particular, the role of the microglia in ALS remains unclear, partly due to the lack of experimental models that can fully recapitulate the complexity of ALS's pathology. In this study, we developed and characterized a microglial cell line, SIM-A9-expressing human mutant protein Cu/Zn superoxide dismutase_1 (SIM-A9hSOD1(G93A)), as a suitable model in vitro mimicking the microglia activity in ALS. The expression of hSOD1(G93A) in SIM-A9 cells induced a change in their metabolic activity, causing polarization into a pro-inflammatory phenotype and enhancing reactive oxygen species production, which is known to activate cell death processes and apoptosis. Afterward, we used our microglial model as an experimental set-up to investigate the therapeutic action of extracellular vesicles isolated from adipose mesenchymal stem cells (ASC-EVs). ASC-EVs represent a promising therapeutic treatment for ALS due to their neuroprotective and immunomodulatory properties. Here, we demonstrated that treatment with ASC-EVs is able to modulate activated ALS microglia, reducing their metabolic activity and polarizing their phenotype toward an anti-inflammatory one through a mechanism of reduction of reactive oxygen species.
Topics: Amyotrophic Lateral Sclerosis; Extracellular Vesicles; Microglia; Mesenchymal Stem Cells; Humans; Superoxide Dismutase-1; Reactive Oxygen Species; Cell Line; Adipose Tissue
PubMed: 38891895
DOI: 10.3390/ijms25115707 -
Cells May 2024Apolipoprotein E (ApoE) is a lipid carrier in both the peripheral and the central nervous systems (CNSs). Lipid-loaded ApoE lipoprotein particles bind to several cell...
Apolipoprotein E (ApoE) is a lipid carrier in both the peripheral and the central nervous systems (CNSs). Lipid-loaded ApoE lipoprotein particles bind to several cell surface receptors to support membrane homeostasis and brain injury repair. In the brain, ApoE is produced predominantly by astrocytes, but it is also abundantly expressed in most neurons of the CNS. In this study, we addressed the role of ApoE in the hippocampus in mice, focusing on its role in response to radiation injury. To this aim, 8-week-old, wild-type, and ApoE-deficient (ApoE) female mice were acutely whole-body irradiated with 3 Gy of X-rays (0.89 Gy/min), then sacrificed 150 days post-irradiation. In addition, age-matching ApoE females were chronically whole-body irradiated (20 mGy/d, cumulative dose of 3 Gy) for 150 days at the low dose-rate facility at the Institute of Environmental Sciences (IES), Rokkasho, Japan. To seek for ApoE-dependent modification during lineage progression from neural stem cells to neurons, we have evaluated the cellular composition of the dentate gyrus in unexposed and irradiated mice using stage-specific markers of adult neurogenesis. Our findings indicate that ApoE genetic inactivation markedly perturbs adult hippocampal neurogenesis in unexposed and irradiated mice. The effect of ApoE inactivation on the expression of a panel of miRNAs with an established role in hippocampal neurogenesis, as well as its transcriptional consequences in their target genes regulating neurogenic program, have also been analyzed. Our data show that the absence of ApoE also influences synaptic functionality and integration by interfering with the regulation of mir-34a, mir-29b, and mir-128b, leading to the downregulation of synaptic markers PSD95 and synaptophysin mRNA. Finally, compared to acute irradiation, chronic exposure of ApoE null mice yields fewer consequences except for the increased microglia-mediated neuroinflammation. Exploring the function of ApoE in the hippocampus could have implications for developing therapeutic approaches to alleviate radiation-induced brain injury.
Topics: Animals; Apolipoproteins E; Hippocampus; Mice; Radiation, Ionizing; Female; MicroRNAs; Mice, Inbred C57BL; Neurons; Neurogenesis; Whole-Body Irradiation; Radiation Exposure; Dentate Gyrus
PubMed: 38891031
DOI: 10.3390/cells13110899 -
Cells May 2024Sleep disruption is a frequent problem of advancing age, often accompanied by low-grade chronic central and peripheral inflammation. We examined whether chronic...
Sleep disruption is a frequent problem of advancing age, often accompanied by low-grade chronic central and peripheral inflammation. We examined whether chronic neuroinflammation in the preoptic and basal forebrain area (POA-BF), a critical sleep-wake regulatory structure, contributes to this disruption. We developed a targeted viral vector designed to overexpress tumor necrosis factor-alpha (TNFα), specifically in astrocytes (AAV5-GFAP-TNFα-mCherry), and injected it into the POA of young mice to induce heightened neuroinflammation within the POA-BF. Compared to the control (treated with AAV5-GFAP-mCherry), mice with astrocytic TNFα overproduction within the POA-BF exhibited signs of increased microglia activation, indicating a heightened local inflammatory milieu. These mice also exhibited aging-like changes in sleep-wake organization and physical performance, including (a) impaired sleep-wake functions characterized by disruptions in sleep and waking during light and dark phases, respectively, and a reduced ability to compensate for sleep loss; (b) dysfunctional VLPO sleep-active neurons, indicated by fewer neurons expressing c-fos after suvorexant-induced sleep; and (c) compromised physical performance as demonstrated by a decline in grip strength. These findings suggest that inflammation-induced dysfunction of sleep- and wake-regulatory mechanisms within the POA-BF may be a critical component of sleep-wake disturbances in aging.
Topics: Animals; Astrocytes; Aging; Preoptic Area; Mice; Tumor Necrosis Factor-alpha; Sleep; Basal Forebrain; Wakefulness; Male; Mice, Inbred C57BL; Neurons; Sleep Wake Disorders
PubMed: 38891027
DOI: 10.3390/cells13110894 -
Cell & Bioscience Jun 2024Neural progenitor cells (NPCs) can be cultivated from developing brains, reproducing many of the processes that occur during neural development. They can be isolated...
BACKGROUND
Neural progenitor cells (NPCs) can be cultivated from developing brains, reproducing many of the processes that occur during neural development. They can be isolated from a variety of animal models, such as transgenic mice carrying mutations in amyloid precursor protein (APP) and presenilin 1 and 2 (PSEN 1 and 2), characteristic of familial Alzheimer's disease (fAD). Modulating the development of these cells with inflammation-related peptides, such as bradykinin (BK) and its antagonist HOE-140, enables the understanding of the impact of such molecules in a relevant AD model.
RESULTS
We performed a global gene expression analysis on transgenic neurospheres treated with BK and HOE-140. To validate the microarray data, quantitative real-time reverse-transcription polymerase chain reaction (RT-PCR) was performed on 8 important genes related to the immune response in AD such as CCL12, CCL5, CCL3, C3, CX3CR1, TLR2 and TNF alpha and Iba-1. Furthermore, comparative analysis of the transcriptional profiles was performed between treatments, including gene ontology and reactome enrichment, construction and analysis of protein-protein interaction networks and, finally, comparison of our data with human dataset from AD patients. The treatments affected the expression levels of genes mainly related to microglia-mediated neuroinflammatory responses, with BK promoting an increase in the expression of genes that enrich processes, biological pathways, and cellular components related to immune dysfunction, neurodegeneration and cell cycle. B2 receptor inhibition by HOE-140 resulted in the reduction of AD-related anomalies caused in this system.
CONCLUSIONS
BK is an important immunomodulatory agent and enhances the immunological changes identified in transgenic neurospheres carrying the genetic load of AD. Bradykinin treatments modulate the expression rates of genes related to microglia-mediated neuroinflammation. Inhibiting bradykinin activity in Alzheimer's disease may slow disease progression.
PubMed: 38890712
DOI: 10.1186/s13578-024-01251-3 -
The Journal of Headache and Pain Jun 2024New onset or worsening of a headache disorder substantially contributes to the disease burden of post-COVID-19. Its management poses a suitable means to enhance...
Occurrence of new or more severe headaches following COVID-19 is associated with markers of microglial activation and peripheral sensitization: results from a prospective cohort study.
BACKGROUND
New onset or worsening of a headache disorder substantially contributes to the disease burden of post-COVID-19. Its management poses a suitable means to enhance patients' participation in professional, social, and personal activities. Unfortunately, the pathophysiology of post-COVID-19 headaches is poorly understood. This study aims to investigate the role of (neuro-) inflammatory mechanisms in order to guide the development of anti-inflammatory treatment strategies.
METHODS
We included patients from the interdisciplinary post-COVID-19 Rehabilitation Study (PoCoRe, n = 184 patients) run at a tertiary care university hospital, comprising patients with PCR-confirmed SARS-CoV-2 infection ≥ 6 weeks prior to their initial consultation. Patients reporting any headache since their infection were considered for this study (n = 93). These were interviewed and classified according to the International Classification of Headache Disorders, Third Edition (ICHD-3) by headache specialists. Patient sera were additionally analysed for levels of VILIP-1, MCP-1 (CCL2), sTREM-2, BDNF, TGF-ß1, VEGF, IL-6, sTREM-1, ß-NGF, IL-18, TNF-alpha, sRAGE, and CX3CL1 (Fractalkine). Markers of inflammation were compared between four groups of patients (none, unchanged, worsened, or new headache disorder).
RESULTS
Patients reported experiencing more severe headaches (n = 17), new onset headaches (n = 46), unchanged headaches (n = 18), and surprisingly, some patients denied having any headaches (n = 12) despite self-reports. Serum levels of CX3CL1 were increased in the worsened (2145 [811-4866] pg/ml) and new onset (1668 [0-7357] pg/ml) headache group as compared to patients with no (1129 [0-5379] pg/ml) or unchanged (1478 [346-4332] pg/ml) headaches. Other markers also differed between groups, but most significantly between patients with worsened (TGF-ß1: 60 [0-310] pg/ml, VEGF: 328 [86-842] pg/ml, ß-NGF: 6 [3-38] pg/ml) as compared to unchanged headaches (TGF-ß1: 29 [0-77] pg/ml, VEGF: 183 [72-380] pg/ml, ß-NGF: 3 [2-89] pg/ml). The results did not differ between headache phenotypes.
DISCUSSION
This study provides evidence that worsened or new headaches following COVID-19 are associated with pro-(neuro-)inflammatory profiles. This supports the use of anti-inflammatory treatment options in this population, especially in the subacute phase.
Topics: Humans; COVID-19; Female; Male; Middle Aged; Prospective Studies; Biomarkers; Adult; Microglia; Headache; Aged; SARS-CoV-2; Cohort Studies; Cytokines
PubMed: 38890625
DOI: 10.1186/s10194-024-01810-6 -
Nature Communications Jun 2024Extracellular ATP (eATP) signaling through the P2X7 receptor pathway is widely believed to trigger NLRP3 inflammasome assembly in microglia, potentially contributing to...
Extracellular ATP (eATP) signaling through the P2X7 receptor pathway is widely believed to trigger NLRP3 inflammasome assembly in microglia, potentially contributing to depression. However, the cellular stress responses of microglia to both eATP and stress itself remain largely unexplored. Mitochondria-associated membranes (MAMs) is a platform facilitating calcium transport between the endoplasmic reticulum (ER) and mitochondria, regulating ER stress responses and mitochondrial homeostasis. This study aims to investigate how MAMs influence microglial reaction and their involvement in the development of depression-like symptoms in response to chronic social defeat stress (CSDS). CSDS induced ER stress, MAMs' modifications, mitochondrial damage, and the formation of the IP3R3-GRP75-VDAC1 complex at the ER-mitochondria interface in hippocampal microglia, all concomitant with depression-like behaviors. Additionally, exposing microglia to eATP to mimic CSDS conditions resulted in analogous outcomes. Furthermore, knocking down GRP75 in BV2 cells impeded ER-mitochondria contact, calcium transfer, ER stress, mitochondrial damage, mitochondrial superoxide production, and NLRP3 inflammasome aggregation induced by eATP. In addition, reduced GRP75 expression in microglia of Cx3cr1Hspa9 mice lead to reduce depressive behaviors, decreased NLRP3 inflammasome aggregation, and fewer ER-mitochondria contacts in hippocampal microglia during CSDS. Here, we show the role of MAMs, particularly the formation of a tripartite complex involving IP3R3, GRP75, and VDAC1 within MAMs, in facilitating communication between the ER and mitochondria in microglia, thereby contributing to the development of depression-like phenotypes in male mice.
Topics: Animals; Mitochondria; Depression; Microglia; Mice; Social Defeat; Male; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Stress, Psychological; Mice, Inbred C57BL; NLR Family, Pyrin Domain-Containing 3 Protein; Voltage-Dependent Anion Channel 1; Hippocampus; Adenosine Triphosphate; Inflammasomes; Inositol 1,4,5-Trisphosphate Receptors; Calcium; Membrane Proteins; Behavior, Animal; Mitochondria Associated Membranes; HSP70 Heat-Shock Proteins
PubMed: 38890305
DOI: 10.1038/s41467-024-49597-z -
Biomedicine & Pharmacotherapy =... Jun 2024Neurodegenerative diseases that include Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), Huntington's disease (HD), and multiple... (Review)
Review
Neurodegenerative diseases that include Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), Huntington's disease (HD), and multiple sclerosis (MS) that arise due to numerous causes like protein accumulation and autoimmunity characterized by neurologic depletion which lead to incapacity in normal physiological function such as thinking and movement in these patients. Glial cells perform an important role in protective neuronal function; in the case of neuroinflammation, glial cell dysfunction can promote the development of neurodegenerative diseases. miRNA that participates in gene regulation and plays a vital role in many biological processes in the body; in the central nervous system (CNS), it can play an essential part in neural maturation and differentiation. In neurodegenerative diseases, miRNA dysregulation occurs, enhancing the development of these diseases. In this review, we discuss neurodegenerative disease (Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS)) and how miRNA is preserved as a diagnostic biomarker or therapeutic agent in these disorders. Finally, we highlight miRNA as therapy.
PubMed: 38889636
DOI: 10.1016/j.biopha.2024.116899